T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

Abstract

We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4 C Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted Tcell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNg, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4C and CD8 C T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.

HER2-LAMP vaccines effectively traffic to endolysosomal compartments and generate enhanced polyfunctional T cell responses that induce complete tumor regression

“…Studies in infectious disease have demonstrated that vaccines capable of producing polyfunctional T cell responses are highly effective, which emerging immunooncology studies have likewise suggested may be critical for effective anti-tumor immunity. [40][41][42][43][44][45] To investigate how LAMP trafficking may generate these enhanced responses, we focused on potential differences in MHC class I and II presentation and resulting CD4+ and CD8+ T cell activation.…”

Anti-Cancer Immunotherapies Targeting Telomerase

“…This approach is based on the adoptive transfer of T cells that are genetically manipulated in order to express TCRs with high affinity for a given tumor antigen. TCR-engineered T cells designed to specifically recognize telomerase have been explored, but current data, although encouraging, are limited to pre-clinical experimental settings [108][109][110][111][112].…”

Transient redirection of T cells for adoptive cell therapy with telomerase-specific T helper cell receptors isolated from long term survivors after cancer vaccination

“…By comparison, the expression of TCR C13 and D71 in primary T cells after retroviral transduction is in our hands 30-60%. 25 As described, TCR D71 is consistently expressed at higher levels than C13 after mRNA transfection, even though the marker gene RQR8 is expressed at similar levels. The difference in expression between C13 and D71 thus appears to be inherent to the TCR.…”

“…23,24 We have previously reported the retroviral cloning and testing of two TCRs, called C13 and D71, against the hTERT-epitope GV1001. 25 Both C13 and D71 recognize peptides presented on DP4, which is the most prevalent HLA-molecule and expressed by >70% of Caucasians. 26 Their common HLA-restriction and the universal expression of hTERT suggest that these TCRs may be widely applicable in a clinical setting.…”